Using Skipped Enynes in [3+3] Annulations with 4-Hydroxycoumarins

Methods for the synthesis of heterocyclic compounds that are step- and atom-economic are useful research targets in organic synthesis. Pd/Brønsted-acid catalyzed additions of nucleophiles to alkynes or skipped enynes, for example, are efficient reaction types that give allyls or 1,3-dienes, respectively. So far, reactants with a single nucleophilic center have generally been used in such reactions with skipped enynes. Using bis-nucleophiles instead could lead to heterocyclic rings in a single transformation: The first nucleophilic addition would lead to a diene, followed by ring closure via an attack involving the second nucleophilic center. However, this type of annulation involving bis-nucleophiles and skipped enynes for the synthesis of heterocycles had not been explored so far.

Shikha Gandhi, Indian Institute of Science Education and Research Berhampur, Odisha, India, and colleagues have developed a method for the [3+3] annulation of skipped enynes with 4-hydroxycoumarins, which act as bis-nucleophiles, to give fused O-heterocycles (example product structure pictured). The team used Pd(PPh₃)₄ as the palladium catalyst together with RuPhos (2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) as a phosphine ligand, PhCOOH as the acid, and a mixture of toluene and tetrahydrofuran (THF) as the solvent. The reactions were performed at 110 °C.

Under these conditions, the researchers obtained a range of annulated products (pyrano[3,2-c]chromenes) in moderate to good yields. The transformation is regioselective. The products are useful for further transformations such as hydrogenations, epoxidations, dihydroxylations, hydrolysis, etc. The team proposes a reaction mechanism that involves the C–H activation of the skipped enynes, leading to the introduction of a 1,3-diene at the 4-hydroxycoumarins, followed by a Pd-catalyzed addition of the second nucleophilic center to the diene to close the new ring.